Palladium-Catalyzed Direct Arylation of Polysubstituted Benzofurans

Article pubs.acs.org/joc

Palladium-Catalyzed Direct Arylation of Polysubstituted Benzofurans Amandine Carrer̈ ,†,‡ Dimitri Brinet,†,‡ Jean-Claude Florent,†,‡ Patricia Rousselle,§ and Emmanuel Bertounesque*,†,‡ †

CNRS UMR 176, 26 rue d’Ulm, 75248 Paris, France Institut Curie, Centre de Recherche, 26 rue d’Ulm, 75248 Paris, France § Institut de Biologie et de Chimie des Protéines, CNRS UMR 5086, 7, passage du Vercors, 69367 Lyon, France ‡

S Supporting Information *

ABSTRACT: An efficient access to 2-substituted 3-arylbenzofurans through a palladium-catalyzed C3 direct arylation of 2-substituted benzofurans with aryl bromides is described. The scope and limitation of this reaction was studied. The method tolerates a variety of functional groups on the aryl halide and has been successfully extended to polysubstituted benzofurans to obtain the corresponding 3-arylbenzofurans with good to excellent yields.

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INTRODUCTION Benzo[b]furan derivatives are an important class of heterocyclic compounds that exhibit biological activity on a wide range of targets.1 Recently, benzofurans have been identified as selective adenosine A2A receptor antagonists2 for a novel nondopaminergic approach to PD therapy, nonacidic benzofuran EP1 receptor antagonists for the treatment of inflammatory pain,3 kinase CK2 inhibitors as antitumor agents,4 antagonists of the CXCR2 receptor as potential use for the treatment of inflammatory and related diseases,5 uric acid transporter 1 (hURAT1) inhibitors with uricosuric activity,6 and agonists of the retinoic acid receptor (RAR) subtypes for cancer therapy and prevention.7 They are found as a key structural unit in many natural products, and pharmaceuticals, such as, for example, amiodarone, befunolol, or bergapten. As part of an ongoing medicinal chemistry project,8 our interest was focused on the synthesis of 3-aryl-2-aroylbenzofurans. Two possible approaches to the construction of this class of compounds have already been described, by acylation of 3-arylbenzofurans9a,b or by condensation of 2-hydroxybenzophenone derivatives with α-bromoarylketones.9c−e However, these approaches required either drastic conditions or multistep synthesis of precursors and gave access to a limited variety of compounds. For these reasons, the developement of a more efficient method to obtain a wider range of polysubstituted benzofurans was needed. 2-Aroylbenzofurans are easily synthesized by Rap−Stoermer condensation from salicylaldehydes and α-bromoketones.10 Recently, this reaction has been extensively studied, and novel applications under microwaves11 or solvent-free12 conditions gave excellent yields with a good tolerance toward functional groups. As an alternative, our investigations were focused on the direct arylation of 2-benzoylbenzofurans at the 3-position as a method for generating 3-aryl-2-benzoylbenzofurans (Scheme 1). Over the past decade, direct arylation has become a powerful alternative to traditional cross-coupling reactions13,14 in order © 2011 American Chemical Society

Scheme 1. Strategy for the Synthesis of 3-Aryl-2aroylbenzofurans

to prepare biaryl molecules. It has also been successfully applied to many heteroaromatic compounds.15 With this new synthetic pathway, there is no more need to preactivate the coupling partner as its halide or organometallic derivative (boron for Suzuki coupling or tin for Stille coupling). Therefore, direct arylation is more atom-economical and environmentally friendly. Up to now, very few examples of C3-arylation of benzofurans have been reported in the literature and only two of them deal with intermolecular arylation.16,17 Indeed, in 2010, Fagnou et al. described the Pd(OAc)2-catalyzed direct arylation of chlorine-containing heteroaromatics, among which only two examples were reported from 2-chlorobenzofuran. The same year, the palladium-catalyzed direct C3-arylation of 2-substituted benzofuran derivatives was published by Doucet et al., a study using Pd(C3H5)Cl(dppb) or Pd(OAc)2 in which few examples with benzofurans bearing electron-withdrawing groups (i.e., acetyl, formyl) at the 2-position are given. On the other hand, it should be noted that arylation of the C−H bonds of benzofuran is regioselective on position 2,18 and in some cases, a C2/C3-diarylation was observed.19 In the quest to expand the knowledge on the reactivity of 2-substituted benzofurans with aryl bromides using Pd(OAc)2, we have studied herein the scope and limitation of the direct arylation with various electron-withdrawing groups (benzoyl, nitro, Received: October 4, 2011 Published: December 5, 2011 1316

dx.doi.org/10.1021/jo202060k | J. Org. Chem. 2012, 77, 1316−1327

The Journal of Organic Chemistry

Article

Table 1. Optimization of Direct Arylation of 2-Benzoylbenzofuran

entry a

1 2a 3a 4a 5a 6b 7a 8b 9b 10b 11b

phosphinec P(t-Bu)2Me PCy3 (10) P(t-Bu)2Me P(t-Bu)2Me P(t-Bu)2Me P(t-Bu)2Me PCy3 (10) PPh3 (10) P(t-Bu)2Me P(t-Bu)2Me P(t-Bu)2Me

(10) (10) (10) (10) (10)

(4) (8) (8)

additive PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH

(30) (30) (60) (120) (60) (30) (60) (30) (30) (30)

solvent

conversion (%)d

DMA DMA DMA DMA Mes Mes Mes Mes Mes Mes Mes

55 11 75 80 95 >95 95 30 85 >95 (90e) 22

a Conditions: 2-benzoylbenzofuran (1 equiv), bromobenzene (2 equiv), Pd(OAc)2 (2 mol %), phosphine (4−10 mol %), Cs2CO3 (2 equiv), and PivOH (30−120 mol %); 150 °C overnight; solvent. bK2CO3 was used as base instead of Cs2CO3. cAlkyl phosphines were used as HBF4 salts. d Determined by 1H NMR. eIsolated yield (%).

cyano, acetyl, tert-butyl-carbonyl, methyl ester) and electrondonating groups (ethyl, phenyl) in the position 2.

2-benzoylbenzofuran were investigated under optimal conditions (Table 2). As general indications, a reaction time from 16 to 63 h was required depending on the aryl bromide used. In several cases (entries 1, 5, 6, 13, 15, and 16), complete conversion of 1 was not observed despite prolonged reaction times. Both electrondonating (entries 1, 4, 5, and 15) and electron-withdrawing (entries 6−14) aryl bromides were found to be reactive, providing the corresponding arylated benzofurans with moderate to excellent yields (37−96%). The method turned out to be tolerant toward a broad range of functional groups, such as nitrile, amide, ester, ether, or amine. The effect of sterical hindrance of the aryl group was then briefly evaluated. Arylation occurred with 1-bromo-2-methylbenzene in 61% yield (entry 15), but no conversion was observed with 2-bromo-1,3dimethylbenzene. Surprisingly, an aryl iodide, such as 1-iodo-4methoxybenzene, did not react with 1 (entry 2), whereas the literature reported many examples of direct arylations using aryl iodides, providing good yields.22 Importantly, Fagnou and coworkers have already observed this phenomenon with aryl iodides and have demonstrated that this behavior is due to catalyst poisoning by the iodide anion.23 Indeed, when Ag2CO3 was added to the reaction involving 1-iodo-4-methoxybenzene in order to sequester iodide anion, the highest yield in 3b (98%) was reached (entry 3 vs entry 1). Direct arylation of benzofuran 1 has also been successfully performed with heteroaryl bromides, such as 2-bromopyridine and 3bromopyridine, to provide the desired coupling products in 23 and 83% yields, respectively (entries 16 and 17). The application of the method to other 2-substituted benzofurans was also examined under the optimized conditions (Table 3, Method A). Benzofurans substituted by electronwithdrawing groups were arylated in good yields (entries 1−3, 5−7). By contrast, no arylation was observed using the same method with benzofurans featuring electron-donating groups (entries 8 and 10), and the starting material was entirely recovered. Thus, to overcome the lack of reactivity in the latter case, another method was developed using the catalytic system Pd(OAc)2/P(t-Bu)2Me·HBF4 with KOAc as a base in DMA

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RESULTS AND DISCUSSION Accordingly, our study began with the optimization of the reaction between 2-benzoylbenzofuran 1 and bromobenzene under various reaction conditions (Table 1). The first attempt was performed under Fagnou direct arylation conditions.16b The catalytic system was composed of Pd(OAc)2, an alkyl-phosphine as its phosphonium tetrafluoroborate salt (P(t-Bu)2Me·HBF4) and pivalic acid as a cocatalyst,20 and cesium carbonate was used as a base (Table 1, entry 1). The reaction was heated at 150 °C in DMA overnight, and 55% of conversion to 3a was then obtained without any degradation or presence of side products. Several bases were screened (K2CO3, KOAc, CsOAc), resulting in little improvement of the conversion rate, but rather in the formation of inseparable byproduct.21 The conversion dropped when the phosphine was changed from P(t-Bu)2Me·HBF4 to PPh3, PEt3·HBF4, or PCy3·HBF4 (entry 2).21 Increasing the proportion of pivalic acid to 60 and 120 mol % allowed an improvement of the conversion from 55% to 75% and 80%, respectively (entries 3 and 4). Conducting the reaction in mesitylene (Mes) gave the best results with a conversion reaching 90% in 8 h, and even 95% after 16 h (entry 5). Prolonged heating had no further effect. Moreover, the optimal conversion was also obtained using 30 mol % pivalic acid in the presence of K2CO3 as a base (entry 6). Without pivalic acid, a significant drop in conversion was observed, which confirms its essential role as a cocatalyst (entry 11). The use of another alkyl phosphine, such as PCy3·HBF4, gave a similar result in mesitylene, in contrast to that in DMA (entry 7 vs entry 2). However, with an aryl phosphine, the conversion decreased to only 30% (entry 8). Decreasing the amount of phosphine to 4 mol % lowered the conversion slightly (85%), and Pd black was observed (entry 9). Finally, reduction of the phosphine amount to 8 mol % led to the optimized reaction conditions (entry 10). To explore the scope and limitation of this method, the coupling reactions between a variety of aryl halides and 1317



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Table 2. Scope of Direct Arylation of 2-Benzoylbenzofuran with Various Aryl and Heteroaryl Bromidesa,b,c

Table 3. Scope of Direct Arylation of 2-Substituted Benzofurans with Aryl Bromidesa,b

a

Method A: benzofuran (1 equiv), arylbromide (2 equiv), Pd(OAc)2 (2 mol %), P(t-Bu)2Me·HBF4 (8 mol %), K2CO3 (2 equiv), and PivOH (30 mol %); 150 °C; mesitylene. Method B: benzofuran (1 equiv), arylbromide (2 equiv), Pd(OAc)2 (2 mol %), P(t-Bu)2Me· HBF4 (8 mol %), and KOAc (2 equiv); 150 °C; DMA. bStarting material yield.

should be noted that a benzofuran substituted with a nonprotected alcohol could be arylated even though in low yield (entry 12). It is noteworthy to point out the specific reactivity of the latter benzofuran when arylation was performed using Method A. Indeed, a one-pot oxidation/arylation sequence occurred to provide 3-phenylbenzofuran-2-carbaldehyde 22j in 79% yield (Table 4, entry 1). It was possible to extend this reaction to the preparation of 3-aryl-2-ketobenzofurans from the corresponding secondary alcohols in very good yields (entries 2 and 3). Importantly, it has been reported that aryl halides could be used as cooxidants in Pd-catalyzed oxidation of primary and secondary alcohols.25 Accordingly, to understand the mechanism of this one-pot transformation, the influence of the aryl bromide on the reactivity was evaluated from benzofuran-2yl(phenyl)methanol 21 (Table 5). First, in the absence of methyl 4-bromobenzoate, 95% of the starting material 21 was recovered, and the ketone 1 was isolated in 5% yield (entry 1). The low yield formation of the latter could result from oxidation of the benzylic alcohol by a

a

Conditions: 2-benzoylbenzofuran (1 equiv), aryl bromide (2 equiv), Pd(OAc)2 (2 mol %), P(t-Bu)2Me·HBF4 (8 mol %), K2CO3 (2 equiv), and PivOH (30 mol %); 150 °C; mesitylene. b1-Iodo-4-methoxybenzene was used instead of 4-bromo-4-methoxybenzene. cAg2CO3 (1 equiv) was added.

(Method B). 24 The arylation reaction could be thus accomplished with 2-ethyl- or 2-phenyl benzofurans in good yields (Table 3, entries 9 and 11). This is a striking result with probable mechanistic consequences (vide infra) since Method B differs from Method A only in that it does not employ pivalate, replaces K2CO3 by KOAc, and uses a polar solvent (DMA). However, these reaction conditions were not well adapted for a benzofuran substituted with an electron-withdrawing group at C2, such as acetyl, as only traces of product were formed, and the reaction led mainly to degradation (entry 4). In addition, it 1318



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arylation (Scheme 2). Several mechanisms have been proposed for direct arylation. In the case of Method A, the difference of reactivity between 2-substituted benzofurans featuring electrondonating groups versus electron-withdrawing groups provided evidence against an SEAr mechanism27 and led us to propose a concerted metalation−deprotonation (CMD) pathway.28 Indeed, it has been shown that the arylation process following this latter route was faster with electron-deficient arenes. Moreover, the influence of pivalic acid has been demonstrated for this method (Table 1, entry 11), and with the CMD mechanism, it has been proposed that the pivalate anion could replace the bromine in the complex Ar−Pd−X, inducing a lower energy of C−H bond cleavage, explaining the key role of pivalic acid as a cocatalyst. As regards to Method B, wherein the palladium source, ligand, reactants, and temperatures are the same as in Method A, it is not obvious why the changes (i.e., no pivalic acid, KOAc, and DMA) would make such a large difference in reactivity, or how Method B fits into the overall mechanistic model. The results suggest another mechanism for electron-rich substrates, possibly the SEAr pathway. This needs to be proven. Finally, given the favorable reactivity of benzofurans substituted by electron-withdrawing groups on position 2 when method A was applied, it was interesting to evaluate its feasibility for the direct arylation of polysubstituted benzofurans. The question arose how the presence of electron-donating groups on the benzenic ring can affect the arylation process of benzofurans. For this purpose, a series of 2-benzoylbenzofurans 23−28 bearing electron-donating groups on positions 4, 5, 6, and/or 7 were synthesized by Rap−Stoermer condensation (Table 6). The required polysubstituted benzofurans were obtained in good to high yields (86−94%) no matter the position and number of substituents (entries 1−5 and 7−9). Subsequent arylation of 23−28 by Method A led to 31−36, respectively (Table 6). The position of the substitution on the benzenic ring turned out to be critical for the yields of the reaction. Indeed, methoxy substituents at positions 5 and 6 (entry 10) or at positions 5, 6, and 7 (entry 11) gave good yields. However, incomplete conversions were achieved with a methoxy substituent at position 4 whatever the presence or not of other methoxy substituents (entries 12−15) and even after a prolonged heating time (16−64 h, entries 12−15). Similar yields were found when this reaction was carried out with hydroxyl or methyl substituents at position 4 (entries 16 and 17). The effects of electron-donating groups at position 4 appear steric in nature, rather than electronic. Indeed, direct arylation on a 2-benzoylbenzofuran substituted by an electron-withdrawing substituent, such as the carbomethoxy group, on position 4 failed, and the starting material was almost entirely recovered (entry 18). By contrast, 2-benzoylbenzofuran substituted by this group on position 7 was arylated in 89% yield (entry 19). These results show that sterical hindrance was an important factor to take into account in C-3 direct arylation of benzofurans. In summary, we have developed a straightforward and efficient access to 2-substituted 3-arylbenzofurans through a palladiumcatalyzed C3 direct arylation of 2-substituted benzofurans with aryl bromides. Electron-donating and electron-withdrawing aryl bromides underwent arylation successfully along with pyridinyl bromides, and the method was compatible with many functional groups. This direct arylation was successfully extended to polysubstituted benzofurans, highlighting its sensitivity to the steric and electronic environment of the benzofuran core.

Table 4. Direct Arylation of Benzofurans Substituted by an Alcohola

a

Method A: 2-substituted benzofuran (1 equiv), aryl bromide 2a or 2j (2 equiv), Pd(OAc)2 (2 mol %), P(t-Bu)2Me·HBF4 (8 mol %), K2CO3 (2 equiv), and PivOH (30 mol %); 150 °C; mesitylene.

Table 5. Influence of the Aryl Bromide on the One-Pot Oxidation/Direct Arylation

yield (%) entry

equiv of 2j

21

1

1 2 3

0 1 2

95

5 89

3j 6 84

catalytic Pd(II) species, typically Pd(OAc)2, according to literature data, with no cooxidant, such as molecular oxygen. With 1 equiv of aryl bromide 2j, the reaction proceeded first by oxidation of the alcohol functionality in 21 to generate benzofuran-2-yl(phenyl)methanone 1 in 89% yield, and subsequent arylation produced phenyl(3-phenylbenzofuran-2-yl)methanone 3j in 6% yield (entry 2). With 2 equiv of the aryl bromide, the arylated ketone 3j was obtained in 84% yield and no C3-arylated alcohol was observed (entry 3). We could thus conclude that alcohol 21 was first oxidized into the corresponding ketone 1, which was then arylated to afford 3j. This result is in full agreement with the fact that the arylation conditions of Method A are only applicable to benzofurans substituted by electron-withdrawing groups at C2. This one-pot reaction oxidation/arylation of benzofurans can be assimilated to an autotandem catalysis according to Fogg et al. classification.26 It involves two distinct catalytic mechanisms promoted by a single catalyst. The first catalytic cycle concerns the oxidation of the alcohol with an aryl halide as a cooxidant, whereas the second catalytic cycle corresponds to the C-3 1319



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Scheme 2. Proposed Mechanism for the One-Pot Oxidation/Arylation of Benzofurans

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acetate 95:5) to afford the desired product 1 (5.45 g, 24.5 mmol, 100%) as a white powder: mp 87 °C (recrystallized from hexane to give white crystals); 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J = 8.4 Hz, 2H), 7.74 (d, J = 8.1 Hz, 1H), 7.67−7.62 (m, 2H), 7.56−7.48 (m, 4H), 7.37−7.31 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 184.4, 156.0, 152.2, 137.2, 132.9, 129.4 (2C), 128.5 (2C), 128.4, 127.0, 124.0, 123.3, 116.5, 112.6; IR (CDCl3) νmax 3068, 1647, 1547, 1330, 1300, 1280, 1187, 1117 cm−1; HRMS (ES+) m/z calculated for C15H11O2 [M + H]+, 223.0759; found, 223.0765. Phenyl(3-phenylbenzofuran-2-yl)methanone 3a. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (222 mg, 1.00 mmol) and bromobenzene (0.12 mL, 2.00 mmol) was stirred for 16 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ ethyl acetate 199:1) twice to afford the desired product 3a (272 mg, 0.91 mmol, 91%) as a pale yellow solid: mp 93 °C (recrystallized from hexane to give pale yellow crystals); 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 7.2 Hz, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.57−7.47 (m, 4H), 7.41−7.32 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 185.8, 154.6, 147.1, 137.2, 132.6, 130.9, 130.0 (2C), 129.8 (2C), 129.4, 128.33 (2C), 128.28, 128.2, 128.0 (2C), 123.9, 122.4, 112.4; IR (CDCl3) νmax 3066, 1648, 1601, 1559, 1492, 1447, 1371, 1292, 1261, 1013 cm−1; HRMS (ES+) m/z calculated for C21H15O2 [M + H]+, 299.1072; found, 299.1079. (3-(4-Methoxyphenyl)benzofuran-2-yl)(phenyl)methanone 3b. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol) and 1-bromo-4-methoxybenzene (0.63 mL, 5.00 mmol) was stirred during 26 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 98:2) to afford the desired product 3b (666 mg, 2.03 mmol, 81%) as a yellow solid: mp 84 °C (recrystallized from hexane); 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 6.9 Hz, 2H), 7.72 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.55−7.44 (m, 4H), 7.39−7.32 (m, 3H), 6.91 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 185.8, 159.7, 154.6, 146.9, 137.3, 132.6, 131.3 (2C), 129.8 (2C), 129.3, 128.2, 128.15, 128.05 (2C), 123.8, 123.0, 122.4, 113.9 (2C), 112.4, 55.3; IR (CDCl3) νmax 3066, 2960, 2839, 1647, 1612, 1560, 1508, 1447, 1375, 1290, 1251, 1175, 1035, 1014 cm−1; HRMS (ES+) m/z calculated for C22H16O3Na [M + Na]+, 351.0997; found, 351.1008. Phenyl(3-(3,4,5-trimethoxyphenyl)benzofuran-2-yl)methanone 3c. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1

EXPERIMENTAL SECTION

General Procedure for Direct Arylation of Benzofurans (Method A). Benzofuran (1 equiv), K2CO3 (2 equiv), P(t-Bu)2 Me·HBF4 (8 mol %), and Pd(OAc)2 (2 mol %) were weighed in air and placed in a screw cap vial equipped with a magnetic stir bar under argon. PivOH (30 mol %) was weighed in air, dissolved in mesitylene, and added to the vial. Aryl halide (2 equiv) was finally added (if liquid, otherwise it was introduced at the beginning with the other solids). The reaction mixture was then vigorously stirred at 150 °C (oil bath temperature) during the indicated time. After cooling to room temperature, the reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography over silica gel to afford the desired product. General Procedure for Direct Arylation of Benzofurans (Method B). Benzofuran (1 equiv), KOAc (2 equiv.), P(t-Bu)2Me· HBF4 (8 mol %), and Pd(OAc)2 (2 mol %) were weighed in air and placed in a screw cap vial equipped with a magnetic stir bar under argon. DMA and the aryl halide (2 equiv) were then added. The reaction was then vigorously stirred at 150 °C (oil bath temperature) during the indicated time. The solution was cooled, diluted with EtOAc, and washed with water. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography over silica gel to afford the desired product. General Procedure for the Rap−Soermer Condensation. To a solution of 2-bromo-1-phenylethanone (1.2 equiv) in acetone was added potassium carbonate (4.0 equiv) and the appropriate 2-hydroxybenzaldehyde (1.0 equiv) under argon. The resulting mixture was stirred at reflux overnight. After removal of the solvent, water and ethyl acetate were added. The aqueous layer was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel to afford the desired product. Benzofuran-2-yl(phenyl)methanone 1. Following the general procedure for Rap−Stoermer condensation, a mixture of 2-bromo-1phenylethanone (5.14 g, 25.8 mmol) and 2-hydroxybenzaldehyde (3.00 g, 24.6 mmol) was stirred at reflux for 20 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl 1320



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Table 6. Direct Arylation of Polysubstituted 2-Benzoylbenzofurans with Bromobenzenea,b,c,d

a

Rap−Stoermer condensation: salicylaldehyde (1 equiv), bromoacetophenone (1.2 equiv), K2CO3 (4 equiv), acetone at reflux overnight. bObtained by deprotection of 25 with BBr3 (2 equiv), dichloromethane at r.t., 4 h. cMethod A: benzofuran (1 equiv), bromobenzene (2 equiv), Pd(OAc)2 (2 mol %), P(t-Bu)2Me·HBF4 (8 mol %), K2CO3 (2 equiv), and PivOH (30 mol %); 150 °C; mesitylene. dNMR yields of the arylated product and starting material (in brackets), calculated from the isolated mixture. H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 7.2 Hz, 2H), 7.79 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.53−7.31 (m, 7H), 6.71 (d, J = 9.0 Hz, 2H), 2.99 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 185.8, 154.7, 150.4, 146.5, 137.6, 132.3, 131.0 (2C), 130.1, 129.8 (2C), 128.4, 128.0 (3C), 123.5, 122.7, 118.1, 112.3, 111.9 (2C), 40.3 (2C); IR (CDCl3) νmax 2926, 2853, 2807, 1645, 1611, 1562, 1514, 1360, 1292, 1164 cm−1; HRMS (ES+) m/z calculated for C23H20NO2 [M + H]+, 342.1494; found, 342.1507. 4-(2-Benzoylbenzofuran-3-yl)benzonitrile 3e. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (222 mg, 1.00 mmol) and 4-bromobenzonitrile (364 mg, 2.00 mmol) was stirred for 18 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 98:2 to 96:4) to afford the desired product 3e (226 mg, 0.70 mmol, 70%) as a white solid: mp 145 °C (recrystallized from hexane/dichloromethane to give white crystals); 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J = 7.2 Hz, 2H), 7.73−7.55 (m, 8H), 7.46−7.37 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 185.1, 154.5, 147.6, 136.8, 136.0, 133.2, 132.1 (2C), 130.7 (2C), 129.9 (2C), 128.6, 128.3 (2C), 127.4, 127.3, 124.5, 121.7, 118.6, 112.6, 112.0; IR (CDCl3) νmax 3067, 2231, 1651, 1612, 1567, 1501, 1371, 1291, 1262, 1014 cm−1; 1

(222 mg, 1.00 mmol) and 5-bromo-1,2,3-trimethoxybenzene (494 mg, 2.00 mmol) was stirred for 40 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 90:10) to afford the desired product 3c (342 mg, 0.88 mmol, 88%) as a yellow solid: mp 104−105 °C (recrystallized from hexane/dichloromethane to give yellow needles); 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J = 6.9 Hz, 2H), 7.76 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.57− 7.45 (m, 2H), 7.40−7.31 (m, 3H), 6.68 (s, 2H), 3.86 (s, 3H), 3.79 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 185.9, 154.6, 153.2 (2C), 147.1, 138.4, 137.5, 132.7, 129.6 (2C), 129.3, 128.3, 128.04 (2C), 127.99, 126.2, 124.0, 122.4, 112.5, 107.7 (2C), 60.8, 56.2 (2C); IR (CDCl3) νmax 3007, 2940, 2834, 1645, 1582, 1560, 1503, 1463, 1416, 1384, 1306, 1282, 1239, 1158, 1130 cm−1; HRMS (ES+) m/z calculated for C24H20O5Na [M + Na]+, 411.1208; found, 411.1227. (3-(4-(Dimethylamino)phenyl)benzofuran-2-yl)(phenyl)methanone 3d. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol) and 4-bromo-N,N-dimethylaniline (1.0 g, 5.00 mmol) was stirred for 40 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 98:2 to 95:5) to afford the desired product 3d (318 mg, 0.93 mmol, 37%) as an orange oil: 1321



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HRMS (ES+) m/z calculated for C22H14NO2 [M + H]+, 324.1025; found, 324.1034. (3-(4-Nitrophenyl)benzofuran-2-yl)(phenyl)methanone 3f. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol) and 1-bromo-4-nitrobenzene (1.01 g, 5.00 mmol) was stirred for 16 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 99:1 to 98:2) to afford the desired product 3f (536 mg, 1.56 mmol, 63%) as an orange solid: mp 162 °C (recrystallized from hexane/dichloromethane to give a pale yellow powder); 1 H NMR (300 MHz, CDCl3) δ 8.30 (d, J = 8.7 Hz, 2H), 7.98 (d, J = 7.2 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H), 7.70−7.64 (m, 2H), 7.61−7.56 (m, 2H), 7.48−7.38 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 185.1, 154.5, 147.7, 147.5, 138.0, 136.8, 133.3, 130.9 (2C), 129.9 (2C), 128.7, 128.4 (2C), 127.3, 127.0, 124.6, 123.6 (2C), 121.6, 112.7; IR (CDCl3) νmax 3070, 1651, 1602, 1560, 1521, 1350, 1292, 1262, 1014 cm−1; HRMS (ES+) m/z calculated for C21H13NO4Na [M + Na]+, 366.0742; found, 366.0755. (3-(4-Chlorophenyl)benzofuran-2-yl)(phenyl)methanone 3g. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (222 mg, 1.00 mmol) and 1-bromo-4-chlorobenzene (383 mg, 2.00 mmol) was stirred for 18 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 199:1) to afford the desired product 3g (315 mg, 0.95 mmol, 95%) as a pale yellow solid: mp 108 °C (recrystallized from hexane to give yellow crystals); 1H NMR (300 MHz, CDCl3) δ 7.92 (d, J = 6.9 Hz, 2H), 7.68−7.63 (m, 2H), 7.57−7.34 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 185.4, 154.5, 147.2, 137.1, 134.4, 132.9, 131.2 (2C), 129.8 (2C), 129.4, 128.6 (2C), 128.4, 128.19 (2C), 128.16, 127.8, 124.1, 122.0, 112.5; IR (CDCl3) νmax 3067, 2955, 1701, 1649, 1601, 1555, 1492, 1370, 1291, 1250, 1092, 1014 cm−1; HRMS (ES+) m/z calculated for C21H14O2Cl [M + H]+, 333.0682; found, 333.0697. Phenyl(3-(4-(trifluoromethyl)phenyl)benzofuran-2-yl)methanone 3h. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (222 mg, 1.00 mmol) and 1-bromo-4-(trifluoromethyl)benzene (0.28 mL, 2.00 mmol) was stirred for 40 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 199:1 to 196:4) to afford the desired product 3h (343 mg, 0.94 mmol, 94%) as a pale yellow solid: mp 135 °C (recrystallized from hexane to give pale yellow crystals); 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J = 7.2 Hz, 2H), 7.68−7.65 (m, 6H), 7.59−7.52 (m, 2H), 7.44−7.36 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 185.3, 154.5, 147.5, 137.0, 134.8, 133.0, 130.31 (q, J = 32 Hz), 130.31 (2C), 129.9 (2C), 128.5, 128.3 (2C), 127.9, 127.7, 125.3 (q, J = 3.8 Hz, 2C), 124.3, 124.0 (q, J = 270 Hz), 121.9, 112.5; IR (CDCl3) νmax 3067, 1650, 1564, 1322, 1292, 1262, 1171, 1132, 1068, 1014 cm−1; HRMS (ES+) m/z calculated for C22H13O2F3Na [M + Na]+, 389.0765; found, 389.0782. 1-(4-(2-Benzoylbenzofuran-3-yl)phenyl)ethanone 3i. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol) and 1-(4-bromophenyl)ethanone (995 mg, 5.00 mmol) was stirred for 23 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 99:1 to 97:3) to afford the desired product 3i (450.5 mg, 1.33 mmol, 53%) as a pale yellow solid: mp 90 °C (recrystallized from hexane/dichloromethane to give yellow crystals); 1 H NMR (300 MHz, CDCl3) δ 8.00 (d, J = 8.7 Hz, 2H), 7.94 (d, J = 7.2 Hz, 2H), 7.69−7.63 (m, 4H), 7.59−7.71 (m, 2H), 7.43−7.36 (m, 3H), 2.64 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 197.6, 185.3, 154.5, 147.5, 137.0, 136.6, 136.0, 133.0, 130.2 (2C), 129.9 (2C), 128.4, 128.3 (2C), 128.24 (2C), 128.18, 127.6, 124.2, 122.0, 112.5, 26.7; IR (CDCl3) νmax 3067, 1683, 1650, 1610, 1567, 1363, 1290, 1266, 1012 cm−1; HRMS (ES+) m/z calculated for C23H17O3 [M + H]+, 341.1178; found, 341.1189. Methyl 4-(2-benzoylbenzofuran-3-yl)benzoate 3j. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol) and methyl 4-bromobenzoate (1.08 g, 5.00 mmol) was stirred for 23 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl

acetate 96:4) to afford the desired product 3j (837 mg, 2.35 mmol, 94%) as a yellow solid: mp 122 °C (recrystallized from hexane/dichloromethane to give yellow needles); 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 7.2 Hz, 2H), 7.69−7.65 (m, 2H), 7.61− 7.49 (m, 4H), 7.41−7.35 (m, 3H), 9.94 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 185.4, 166.7, 154.6, 147.4, 137.0, 135.8, 133.0, 130.0 (2C), 129.9 (2C), 129.8, 129.6 (2C), 128.4, 128.2 (3C), 127.7, 124.2, 122.0, 112.5, 52.2; IR (CDCl3) νmax 3067, 2954, 1719, 1650, 1612, 1571, 1438, 1289, 1114, 1014 cm−1; HRMS (ES+) m/z calculated for C23H16O4Na [M + Na]+, 379.0946; found, 379.0959. (4-(2-Benzoylbenzofuran-3-yl)phenyl)(morpholino)methanone 3k. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (222 mg, 1.00 mmol) and (4-bromophenyl)(morpholino)methanone (540 mg, 2.00 mmol) was stirred for 24 h. The residue was purified by flash chromatography over silica gel (dichloromethane/methanol 99:1) to afford the desired product 3k (397 mg, 0.96 mmol, 96%) as a white solid: mp 254 °C (recrystallized from hexane/dichloromethane); 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 7.2 Hz, 2H), 7.69−7.64 (m, 2H), 7.60−7.35 (m, 9H), 3.73−7.48 (m, 8H); 13C NMR (75 MHz, CDCl3) δ 185.6, 169.9, 154.6, 147.3, 137.2, 135.1, 132.7 (2C), 130.2 (2C), 129.9 (2C), 128.4, 128.2 (3C), 127.8, 127.1 (2C), 124.2, 122.1, 112.5, 66.9 (4C); IR (CDCl3) νmax 3067, 2924, 2861, 1630, 1568, 1433, 1280, 1261, 1114, 1013 cm−1; HRMS (ES+) m/z calculated for C26H22NO4 [M + H]+, 412.1549; found, 412.1566. (3-(3-Fluorophenyl)benzofuran-2-yl)(phenyl)methanone 3l. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol) and 1-bromo-4-chlorobenzene (0.64 mL, 5.00 mmol) was stirred for 48 h. The residue was purified twice by flash chromatography over silica gel (cyclohexane/ethyl acetate 199:1) to afford the desired product 3l (468 mg, 1.48 mmol, 59%) as a pale yellow solid: mp 58 °C (recrystallized from hexane to give a pale yellow powder); 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 7.5 Hz, 2H), 7.71−7.64 (m, 2H), 7.57−7.50 (m, 2H), 7.42−7.22 (m, 6H), 7.09−7.02 (m, 1H); 13 C NMR (75 MHz, CDCl3) δ 185.5, 162.6 (d, J = 245 Hz), 154.5, 147.3, 137.1, 133.0 (d, J = 8.4 Hz), 132.9, 129.9 (d, J = 8.3 Hz), 129.8 (2C), 128.4, 128.2 (2C), 128.0 (d, J = 2.4 Hz), 127.7, 125.8 (d, J = 2.9 Hz), 124.1, 122.1, 116.9 (d, J = 22.3 Hz), 115.3 (d, J = 20.9 Hz), 112.5; IR (CDCl3) νmax 3068, 1650, 1614, 1563, 1448, 1292, 1262, 1233, 1168, 1021 cm−1; HRMS (ES+) m/z calculated for C21H14O2F [M + H]+, 317.0978; found, 317.0991. (3-(4-Fluorophenyl)benzofuran-2-yl)(phenyl)methanone 3m. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (222 mg, 1.00 mmol) and 1-bromo-4-fluorobenzene (0.22 mL, 2.00 mmol) was stirred during 21 h. The residue was purified twice by flash chromatography over silica gel (cyclohexane/ethyl acetate 199:1) to afford the desired product 3m (267 mg, 0.84 mmol, 84%) as a pale yellow solid: mp 80 °C (recrystallized from hexane to give a pale yellow powder); 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 7.2 Hz, 2H), 7.69−7.64 (m, 2H), 7.57−7.48 (m, 4H), 7.41−7.34 (m, 3H), 7.08 (t, J = 9.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 185.6, 162.7 (d, J = 247 Hz), 154.5, 147.2, 137.2, 132.8, 131.75 (d, J = 8.2 Hz, 2C), 129.8 (2C), 128.4, 128.3, 128.1 (2C), 128.0, 126.8 (d, J = 3.4 Hz), 124.0, 122.1, 115.4 (d, J = 21.5 Hz, 2C), 112.4; IR (CDCl3) νmax 3066, 2959, 1649, 1601, 1563, 1506, 1374, 1292, 1261, 1227, 1161, 1014 cm−1; HRMS (ES+) m/z calculated for C21H14O2F [M + H]+, 317.0978; found, 317.0982. Phenyl(3-o-tolylbenzofuran-2-yl)methanone 3n. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (222 mg, 1.00 mmol) and 1bromo-2-methylbenzene (0.24 mL, 2.00 mmol) was stirred for 24 h. The residue was purified twice by flash chromatography over silica gel (cyclohexane/ethyl acetate 199:1) to afford the desired product 3n (190 mg, 0.61 mmol, 61%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.91 (d, J = 6.9 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.56−7.19 (m, 10H), 2.17 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 185.3, 154.5, 147.8, 137.1, 136.8, 132.6, 130.7, 130.2 (2C), 129.6 (2C), 129.1, 128.6, 128.3, 128.2, 128.0 (2C), 125.6, 123.8, 122.6, 112.4, 20.0; IR (CDCl3) 1322



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νmax 2926, 1647, 1601, 1560, 1368, 1334, 1294, 1011 cm−1; HRMS (ES+) m/z calculated for C22H17O2 [M + H]+, 313.1229; found, 313.1231. Phenyl(3-(pyridin-2-yl)benzofuran-2-yl)methanone 3o. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol) and 2-bromopyridine (0.48 mL, 5.00 mmol) was stirred for 63 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 90:10) to afford the desired product 3o (170 mg, 0.57 mmol, 23%) as a pale yellow solid: mp 87 °C (recrystallized from hexane/dichloromethane to give pale yellow crystals); 1H NMR (300 MHz, CDCl3) δ 8.70 (dt, J = 4.8, 1.5 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 7.2 Hz, 2H), 7.67−7.60 (m, 3H), 7.56−7.48 (m, 2H), 7.41−7.34 (m, 3H), 7.26−7.21 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 185.9, 154.7, 150.9, 149.6, 148.1, 137.2, 136.0, 132.9, 129.9 (2C), 128.16 (2C), 128.14, 127.9, 127.4, 125.9, 124.2, 123.2, 122.7, 112.2; IR (CDCl3) νmax 3064, 1651, 1595, 1563, 1464, 1369, 1293, 1260, 1168, 1018 cm−1; HRMS (ES+) m/z calculated for C20H14NO2 [M + H]+, 300.1025; found, 300.1028. Phenyl(3-(pyridin-3-yl)benzofuran-2-yl)methanone 3p. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-yl(phenyl)methanone 1 (555 mg, 2.50 mmol) and 3-bromopyridine (0.48 mL, 5.00 mmol) was stirred for 63 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 70:30) to afford the desired product 3p (622 mg, 2.08 mmol, 83%) as a white solid: mp 125 °C (recrystallized from hexane/dichloromethane to give white crystals); 1H NMR (300 MHz, CDCl3) δ 8.79 (d, J = 1.8 Hz, 1H), 8.62 (dd, J = 4.8, 1.5 Hz, 1H), 7.95 (d, J = 7.2 Hz, 2H), 7.90 (dt, J = 7.8, 2.1 Hz, 1H), 7.70−7.66 (m, 2H), 7.60−7.53 (m, 2H), 7.45−7.33 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 185.2, 154.5, 150.3, 149.3, 147.7, 137.4, 136.9, 133.0, 129.9 (2C), 128.6, 128.3 (2C), 127.6, 127.3, 125.9, 124.3, 123.1, 121.8, 112.6; IR (CDCl3) νmax 3064, 1650, 1600, 1555, 1371, 1292, 1262, 1229, 1013 cm−1; HRMS (ES+) m/z calculated for C20H13NO2Na [M + Na]+, 322.0844; found, 322.0856. Methyl 4-(2-nitrobenzofuran-3-yl)benzoate 12j. Following the general procedure for direct arylation (Method A), a mixture of 2-nitrobenzofuran 429 (147 mg, 0.90 mmol) and methyl 4-bromobenzoate (387 mg, 2.00 mmol) was stirred during 20 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 95:5) to afford the desired product 12j (207 mg, 0.70 mmol, 77%) as an orange solid: mp 154 °C (recrystallized from hexane/ dichloromethane to give an orange powder); 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J = 8.4 Hz, 2H), 7.71−7.61 (m, 5H), 7.44 (ddd, J = 8.1, 6.0, 2.1 Hz, 1H), 3.98 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.4, 151.7 (2C), 132.8, 131.1, 130.5, 130.0 (2C), 129.8 (2C), 127.2, 125.5, 123.1, 121.3, 112.7, 52.4; IR (CDCl3) νmax 3002, 2954, 2848, 1722, 1525, 1373, 1325, 1282, 1113 cm−1; HRMS (ES+) m/z calculated for C16H11NO5Na [M + Na]+, 320.0535; found, 320.0538. Methyl 4-(2-cyano-6-methoxybenzofuran-3-yl)benzoate 13j. Following the general procedure for direct arylation (Method A), a mixture of 6-methoxybenzofuran-2-carbonitrile 530 (173 mg, 1.00 mmol) and methyl 4-bromobenzoate (430 mg, 2.00 mmol) was stirred for 23 h. The residue was purified by flash chromatography over silica gel (cyclohexane/dichloromethane 50:50) to afford the desired product 13j (250 mg, 0.81 mmol, 81%) as a white solid: mp 197 °C; 1H NMR (300 MHz, CDCl3) δ 8.22 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 9.3 Hz, 1H), 7.06−7.04 (m, 2H), 3.97 (s, 3H), 3.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.4, 161.5, 157.3, 133.2, 132.4, 130.9, 130.5 (2C), 128.3 (2C), 123.0, 121.9, 117.9, 115.2, 112.5, 95.7, 55.9, 52.4; IR (CDCl3) νmax 2954, 2842, 2225, 1722, 1619, 1496, 1436, 1286, 1196, 1154, 1115 cm−1; HRMS (ES+) m/z calculated for C18H13NO4Na [M + Na]+, 330.0742; found, 330.0755. Methyl 4-(2-acetylbenzofuran-3-yl)benzoate 14j. Following the general procedure for direct arylation (Method A), a mixture of 1-(benzofuran-2-yl)ethanone 631 (160 mg, 1.00 mmol) and methyl 4-bromobenzoate (430 mg, 2.00 mmol) was stirred for 23 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 95:5) to afford the desired product 14j (164 mg, 0.56 mmol, 56%) as a pale yellow solid: mp 195 °C (recrystallized from

hexane/dichloromethane to give a pale yellow powder); 1H NMR (300 MHz, CDCl3) δ 8.18 (d, J = 8.4 Hz, 2H), 7.68−7.51 (m, 5H), 7.36− 7.31 (m, 1H), 3.97 (s, 3H), 2.56 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 189.7, 166.7, 154.1, 147.2, 135.6, 130.2, 130.0 (2C), 129.6 (2C), 128.6, 128.2, 126.5, 124.1, 122.2, 112.4, 52.2, 28.2; IR (CDCl3) νmax 3004, 2954, 1719, 1683, 1572, 1438, 1287, 1116, 1106 cm−1; HRMS (ES+) m/z calculated for C18H14O4Na [M + Na]+, 317.0790; found, 317.0795. Methyl 4-(2-pivaloylbenzofuran-3-yl)benzoate 15j. Following the general procedure for direct arylation (Method A), a mixture of 1-(benzofuran-2-yl)-2,2-dimethylpropan-1-one 732 (202 mg, 1.00 mmol) and methyl 4-bromobenzoate (430 mg, 2.00 mmol) was stirred for 24 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 99:1 to 97:3) to afford the desired product 15j (229 mg, 0.68 mmol, 68%) as a white solid: mp 82 °C (recrystallized from hexane to give white crystals); 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J = 8.4 Hz, 2H), 7.63−7.59 (m, 3H), 7.55−7.50 (m, 2H), 7.35−7.30 (m, 1H), 3.95 (s, 3H), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 197.5, 166.8, 153.6, 147.1, 136.3, 129.9 (2C), 129.7, 129.5 (2C), 128.1, 127.8, 123.9, 121.9, 112.1, 52.2, 44.2, 26.4 (3C); IR (CDCl3) νmax 2956, 2909, 2875, 1719, 1673, 1613, 1559, 1438, 1281, 1183, 1114, 1053 cm−1; HRMS (ES+): m/z calculated for C21H21O4 [M + H]+, 337.1440; found, 337.1449. Methyl 3-phenylbenzofuran-2-carboxylate 16a. Following the general procedure for direct arylation (Method A), a mixture of methyl benzofuran-2-carboxylate 833 (440 mg, 2.50 mmol) and bromobenzene (0.53 mL, 5.00 mmol) was stirred for 15 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ ethyl acetate 95:5) to afford the desired product 16a (582.5 mg, 2.31 mmol, 92%) as a white solid: mp 92 °C (recrystallized from hexane to give a white powder); 1H NMR (300 MHz, CDCl3) δ 7.65− 7.58 (m, 4H), 7.54−7.45 (m, 4H), 7.35−7.29 (m, 1H), 3.89 (s, 3H); 13 C NMR (75 MHz, CDCl3) δ 160.2, 154.5, 139.8, 130.5, 129.9 (2C), 129.5, 128.5, 128.3, 128.2 (2C), 128.1, 123.8, 122.1, 112.3, 52.1; IR (CDCl3) νmax 3036, 2954, 1723, 1579, 1496, 1439, 1376, 1295, 1267, 1226, 1157, 1141 cm−1; HRMS (ES+) m/z calculated for C16H12O3Na [M + Na]+, 275.0684; found, 275.0686. Methyl 3-(4-(methoxycarbonyl)phenyl)benzofuran-2-carboxylate 16j. Following the general procedure for direct arylation (Method A), a mixture of methyl benzofuran-2-carboxylate 8 (176 mg, 1.00 mmol) and methyl 4-bromobenzoate (430 mg, 2.00 mmol) was stirred during 23 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 95:5) to afford the desired product 16j (241.6 mg, 0.78 mmol, 78%) as a white solid: mp 127 °C (recrystallized from hexane/dichloromethane); 1H NMR (300 MHz, CDCl3) δ 8.17 (d, J = 8.4 Hz, 2H), 7.68−7.63 (m, 3H), 7.58−7.49 (m, 2H), 7.33 (t, J = 8.1 Hz, 1H), 3.97 (s, 3H), 3.88 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.8, 160.0, 154.5, 140.1, 135.3, 130.1, 130.0 (2C), 129.5 (2C), 128.4, 128.3, 127.8, 124.1, 121.8, 112.4, 52.5 (2C); IR (CDCl3) νmax 3003, 2954, 2360, 1722, 1614, 1590, 1438, 1376, 1291, 1142, 1110 cm−1; HRMS (ES+) m/z calculated for C18H15O5 [M + H]+, 311.0919; found, 311.0928. 2-Ethyl-3-phenylbenzofuran 17a.34 Following the general procedure for direct arylation (Method B), a mixture of 2-ethylbenzofuran 9 (146 mg, 1.0 mmol) and bromobenzene (0.210 mL, 2.0 mmol) was stirred for 16 h. The residue was purified by flash chromatography over silica gel (pentane) to afford the desired product 17a (153 mg, 0.69 mmol, 69%) as a transparent liquid: 1H NMR (300 MHz, CDCl3) δ 7.62−7.59 (m, 1H), 7.54−7.47 (m, 5H), 7.41−7.36 (m, 1H), 7.32− 7.21 (m, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.39 (q, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 156.1, 154.0, 132.8, 129.0 (2C), 128.8, 128.7 (2C), 126.9, 123.5, 122.5, 119.4, 116.1, 110.8, 20.2, 12.9; IR (CDCl3) νmax 3062, 2979, 2939, 1612, 1456, 1241, 1196, 1176 cm−1; MS (ES+) m/z 245 [M + Na]+. 2,3-Diphenylbenzofuran 18a.35 Following the general procedure for direct arylation (Method B), a mixture of 2-phenylbenzofuran 1036 (97 mg, 0.50 mmol) and bromobenzene (0.105 mL, 1.00 mmol) was stirred for 16 h. The residue was purified by flash chromatography over silica gel (pentane) to afford the desired product 18a (93 mg, 0.345 mmol, 69%) as a white solid: mp 123 °C (recrystallized from 1323



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hexane to give white crystals) (lit. mp 123 °C); 1H NMR (300 MHz, CDCl3) δ 7.68−7.65 (m, 2H), 7.56 (d, J = 7.8 Hz, 1H), 7.53−7.30 (m, 10H), 7.27−7.22 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 153.9, 150.5, 132.8, 130.6, 130.2, 129.7 (2C), 128.9 (2C), 128.4 (2C), 128.3, 127.6, 127.0 (2C), 124.6, 122.9, 120.0, 117.4, 111.1; IR (CDCl3) νmax 3064, 3037, 1604, 1503, 1455, 1443, 1258, 1207, 1064, 1028 cm−1; MS (ES+) m/z 293 [M + Na]+. (3-Phenylbenzofuran-2-yl)methanol 19a.37 Following the general procedure for direct arylation (Method B), a mixture of benzofuran-2-ylmethanol 1138 (148 mg, 1.00 mmol) and bromobenzene (0.21 mL, 2.00 mmol) was stirred for 16 h. The residue was purified by flash chromatography over silica gel (dichloromethane) to afford the desired product 19a (40 mg, 0.18 mmol, 18%) as a yellow solid: mp 79 °C (recrystallized from hexane to give white crystals); 1 H NMR (300 MHz, CDCl3) δ 7.67−7.64 (m, 1H), 7.58−7.48 (m, 5H), 7.44−7.33 (m, 2H), 7.30−7.25 (m, 1H), 4.84 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 154.3, 151.6, 131.6, 129.1 (2C), 128.9 (2C), 127.9, 127.6, 124.9, 123.0, 120.4, 119.8, 111.4, 56.4; IR (CDCl3) νmax 3608, 3063, 2930, 2874, 1613, 1454, 1262, 1222, 1177, 1016 cm−1; MS (ES+) m/z 247 [M + Na]+. Methyl 4-(2-formylbenzofuran-3-yl)benzoate 22j. Following the general procedure for direct arylation (Method A), a mixture of benzofuran-2-ylmethanol 11 (148 mg, 1.00 mmol) and methyl 4-bromobenzoate (430 mg, 2.00 mmol) was stirred for 23 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 95:5) to afford the desired product 22j (220 mg, 0.79 mmol, 79%) as a white solid: mp 136 °C (recrystallized from hexane/dichloromethane to give a white powder); 1H NMR (300 MHz, CDCl3) δ 9.90 (s, 1H), 8.24 (d, J = 8.7 Hz, 2H), 7.77−7.67 (m, 4H), 7.63−7.57 (m, 1H), 7.43−7.38 (m, 1H), 3.99 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 179.5, 166.4, 155.4, 147.8, 133.8, 132.5, 131.0, 130.3 (2C), 130.0 (2C), 129.8, 126.8, 124.5, 122.4, 112.9, 52.4; IR (CDCl3) νmax 2954, 2853, 1722, 1673, 1287, 1115 cm−1; HRMS (ES+) m/z calculated for C17H13O4 [M + H]+, 281.0814; found, 281.0822. 1-(3-Phenylbenzofuran-2-yl)ethanone 14a.39 Following the general procedure for direct arylation (method A), a mixture of 1-(benzofuran-2-yl)ethanol 2040 (405 mg, 2.50 mmol) and bromobenzene (0.53 mL, 5.00 mmol) was stirred for 17 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 99:1 to 95:5) to afford a mixture of the desired product 14a (566 mg, 2.40 mmol, 96%) as a yellow solid: mp 95 °C (recrystallized from hexane to give white crystals); 1H NMR (300 MHz, CDCl3) δ 7.63−7.46 (m, 8H), 7.34−7.28 (m, 1H), 2.49 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 189.6, 154.1, 147.1, 130.8, 129.9 (2C), 128.7, 128.44 (2C), 128.42, 127.9, 123.8, 122.5, 112.2, 28.3; IR (CDCl3) νmax 3066, 3035, 1680, 1562, 1494, 1375, 1290, 1214, 1103 cm−1; MS (ES+) m/z 259 [M + Na]+. (5,6-Dimethoxybenzofuran-2-yl)(phenyl)methanone 23. Following the general procedure for Rap−Stoermer condensation, a mixture of 2-bromo-1-phenylethanone (1.15 g, 5.80 mmol) and 2-hydroxy-4,5-dimethoxybenzaldehyde (1.00 g, 5.49 mmol) was stirred at reflux for 16 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 80:20 to 70:30) to afford the desired product 23 (1.39 g, 4.93 mmol, 90%) as a yellow solid: mp 130 °C (recrystallized from heptane/ethyl acetate to give a yellow powder); 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 7.2 Hz, 2H), 7.65−7.59 (m, 1H), 7.53 (t, J = 7.2 Hz, 2H), 7.46 (d, J = 0.9 Hz, 1H), 7.13 (s, 1H), 7.07 (s,1H), 3.98 (s, 3H), 3.94 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 183.5, 151.9, 151.8, 151.77, 147.7, 137.5, 132.5, 129.3 (2C) 128.4 (2C), 119.1, 117.4, 102.6, 95.1, 56.3 (2C); IR (CDCl3) νmax 2964, 2941, 2837, 1638, 1541, 1490, 1296, 1252, 1234, 1214, 1197, 1120 cm−1; HRMS (ES+) m/z calculated for C17H15O4 [M + H]+, 283.0977; found, 283.0970. Phenyl(5,6,7-trimethoxybenzofuran-2-yl)methanone 24. Following the general procedure for Rap−Stoermer condensation, a mixture of 2-bromo-1-phenylethanone (0.98 g, 4.94 mmol) and 2-hydroxy-4,5,6-trimethoxybenzaldehyde (1.00 g, 4.72 mmol) was stirred at reflux for 16 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 85:15 to 80:20) to afford the desired product 24 (1.27 g, 4.07 mmol, 86%) as a brown

solid: mp 92 °C (recrystallized from hexane to give a white product); H NMR (300 MHz, CDCl3) δ 8.04 (d, J = 6.9 Hz, 2H), 7.66− 7.60 (m, 1H), 7.53 (t, J = 6.9 Hz, 2H),7.48 (s, 1H), 6.82 (s, 1H), 4.27 (s, 3H), 3.96 (s, 3H), 3.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 183.5, 152.8, 151.8, 143.2, 142.0, 139.3, 137.3, 132.7, 129.4 (2C), 128.4 (2C), 123.1, 116.7, 97.2, 61.6, 61.0, 56.3; IR (CDCl3) νmax 3006, 2940, 2835, 1645, 1553, 1486, 1357, 1302, 1256, 1226, 1124 cm−1; HRMS (ES+) m/z calculated for C18H17O5 [M + H]+, 313.1076; found, 313.1077. Phenyl(4,5,6-trimethoxybenzofuran-2-yl)methanone 25. Following the general procedure for Rap−Stoermer condensation, a mixture of 2-bromo-1-phenylethanone (0.98 g, 4.94 mmol) and 2-hydroxy-4,5,6-trimethoxybenzaldehyde (1.00 g, 4.72 mmol) was stirred at reflux for 17.5 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 90:10 to 80:20) to afford the desired product 25 (1.34 g, 4.30 mmol, 91%) as a yellow powder: mp 90 °C (recrystallized from hexane to give a white product); 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J = 7.2 Hz, 2H), 7.65−7.59 (m, 2H), 7.53 (t, J = 7.2 Hz, 2H), 6.87 (s, 1H), 4.13 (s, 3H), 3.95 (s, 3H), 3.87 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 183.5, 156.0, 153.5, 151.0, 147.2, 137.5, 137.4, 132.6, 129.2 (2C), 128.5 (2C), 115.7, 113.4, 90.2, 61.4, 61.3, 56.4; IR (CDCl3) νmax 2967, 2940, 1641, 1649, 1541, 1485, 1469, 1301, 1274, 1200, 1152, 1129 cm−1; HRMS (ES+) m/z calculated for C18H17O5 [M + H]+, 313.1076; found, 313.1082. (4-Methoxybenzofuran-2-yl)(phenyl)methanone 26. Following the general procedure for Rap−Stoermer condensation, a mixture of 2-bromo-1-phenylethanone (1.36 g, 6.83 mmol) and 2-hydroxy-4methoxy-benzaldehyde (1.00 g, 6.50 mmol) was stirred at reflux for 16.5 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 95:5 to 90:10) to afford the desired product 26 (1.54 g, 6.10 mmol, 94%) as a white powder: mp 100 °C (recrystallized from heptane to give white crystals); 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J = 7.2 Hz, 2H), 7.66−7.61 (m, 2H), 7.53 (t, J = 7.2 Hz, 2H), 7.43 (t, J = 8.1 Hz, 1H), 7.26−7.23 (m, 1H), 6.71 (d, J = 7.8 Hz, 1H), 3.97 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 184.1, 157.1, 155.1, 150.9, 137.3, 132.7, 129.5, 129.3 (2C), 128.5 (2C), 118.0, 114.7, 105.2, 103.5, 55.6; IR (CDCl3) νmax 2965, 2946, 2842, 1646, 1542, 1498, 1339, 1266, 1134, 1089 cm−1; HRMS (ES+) m/z calculated for C16H13O3 [M + H]+, 253.0865; found, 253.0874. (4-Hydroxybenzofurane-2-yl)(phenyl)methanone 27. To a solution of (4-methoxybenzofuran-2-yl)(phenyl)methanone 26 (100 mg, 0.40 mmol, 1.0 equiv) in dichloromethane was added a solution of boron tribromide in dichloromethane (0.80 mL, 0.80 mmol, 2.0 equiv) under argon at 0 °C. The resulting mixture was stirred at room temperature for 4 h. After quenching with water, saturated Na2CO3 solution was added until pH = 7. The aqueous layer was extracted two times with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 90:10) to afford the desired product 27 (46 mg, 0.19 mmol, 48%) as a brown powder: mp 180 °C (recrystallized from hexane/ethyl acetate to give brown crystals); 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J = 6.9 Hz, 2H), 7.68 (s, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.52 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 6.04 (s, 1H); 13 C NMR (75 MHz, CDCl3) δ 184.9, 158.0, 151.7, 151.5, 137.6, 133.4, 130.0, 129.9 (2C), 129.0 (2C), 117.6, 115.0, 108.8, 105.5; IR (CDCl3) νmax 3359, 3066, 1648, 1622, 1603, 1544, 1342, 1274, 1180 cm−1; HRMS (ES+) m/z calculated for C15H11O3 [M + H]+, 239.0708; found, 239.0700. (4,6-Dimethylbenzofuran-2-yl)(phenyl)methanone 28. Following the general procedure for Rap−Stoermer condensation, a mixture of 2-bromo-1-phenylethanone (0.70 g, 3.50 mmol) and 2-hydroxy-4,6-dimethylbenzaldehyde (0.50 g, 3.33 mmol) was stirred at reflux for 16 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 95:5 to 90:10) to afford the desired product 28 (0.83 g, 3.32 mmol, 100%) as a yellow solid: mp 77 °C (recrystallized from hexane to give yellow crystals); 1H NMR (300 MHz, CDCl3) δ 8.03 (d, J = 6.9 Hz, 2H), 7.67−7.61 (m, 1H), 1

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7.57−7.50 (m, 3H), 7.26 (s, 1H), 6.96 (s, 1H), 2.52 (s, 3H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 184.3, 156.6, 151.4, 139.5, 137.5, 133.0, 132.6, 129.3 (2C), 128.5 (2C), 125.9, 124.7, 115.7, 109.8, 22.0, 18.5; IR (CDCl3) νmax 3028, 2921, 1642, 1539, 1343, 1270 cm−1; HRMS (ES+) m/z calculated for C17H15O2 [M + H]+, 251.1072; found, 251.1063. Methyl 2-benzoylbenzofuran-4-carboxylate 29. Following the general procedure for Rap−Stoermer condensation, a mixture of 2-bromo-1-phenylethanone (829 mg, 4.16 mmol) and methyl 2-formyl-3-hydroxybenzoate (500 mg, 2.78 mmol) was stirred at reflux for 20 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 95:5) to afford the desired product 29 (643 mg, 2.30 mmol, 83%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.09−8.05 (m, 4H), 7.86 (d, J = 8.4 Hz, 1H), 7.69−7.64 (m, 1H), 7.60−7.54 (m, 3H), 4.00 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 184.2, 166.0, 155.9, 152.9, 136.8, 133.0, 129.4 (2C), 128.5 (2C), 127.4, 127.0, 126.5, 124.6, 117.0, 116.8, 52.1; IR (CDCl3) νmax 3067, 3002, 2954, 1718, 1650, 1600, 1544, 1438, 1331, 1289, 1274, 1208, 1169, 1120 cm−1; HRMS (ES+) m/z calculated for C17H13O4 [M + H]+, 281.0814; found, 281.0805. Methyl 2-benzoylbenzofuran-7-carboxylate 30. Following the general procedure for Rap−Stoermer condensation, a mixture of 2-bromo-1-phenylethanone (1.20 g, 5.84 mmol) and methyl 3-formyl2-hydroxybenzoate (1.00 g, 5.56 mmol) was stirred at reflux for 16 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 98:2) to afford the desired product 30 (0.944 g, 3.40 mmol, 61%) as a yellow solid: mp 75 °C (recrystallized from hexane to give a white product); 1H NMR (300 MHz, CDCl3) δ 8.28 (d, J = 7.2 Hz, 2H), 8.19 (dd, J = 7.5, 1.2 Hz, 1H), 7.95 (dd, J = 8.1, 1.2 Hz, 1H), 7.69−7.64 (m, 2H), 7.59−7.54 (m, 2H), 7.43 (t, J = 7.8 Hz, 1H), 4.06 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 183.3, 164.9, 153.8, 153.6, 136.5, 133.2, 130.6, 129.9 (2C), 128.51, 128.48 (2C), 128.2, 123.7, 116.1, 114.9, 52.5; IR (CDCl3) νmax 3072, 2954, 1721, 1650, 1600, 1556, 1296, 1217, 1143 cm−1; HRMS (ES+) m/z calculated for C17H13O4 [M + H]+, 281.0814; found, 281.0800. (5,6-Dimethoxy-3-phenylbenzofuran-2-yl)(phenyl)methanone 31. Following the general procedure for direct arylation, a mixture of (5,6-dimethoxybenzofuran-2-yl)(phenyl)methanone 23 (282 mg, 1.00 mmol) and bromobenzene (0.21 mL, 2.00 mmol) was stirred for 16 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 80:20 to 75:25) to afford the desired product 31 (279 mg, 0.78 mmol, 78%) as a brown solid: mp 109 °C (recrystallized from hexane to give a yellow powder); 1H NMR (300 MHz, CDCl3) δ 7.84 (d, J = 6.9 Hz, 2H), 7.49−7.41 (m, 3H), 7.40−7.30 (m, 5H), 7.13 (s, 1H), 6.99 (s, 1H), 3.99 (s, 3H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 184.8, 151.8, 150.2, 147.9, 146.9, 137.6, 132.2, 131.3, 130.5, 129.8 (2C), 129.7 (2C), 128.3 (2C), 128.2, 127.9 (2C), 120.1, 101.7, 95.0, 56.4 (2C); IR (CDCl3) νmax 2963, 2940, 2836, 1637, 1552, 1492, 1302, 1256, 1223, 1135 cm−1; HRMS (ES+) m/z calculated for C23H19O4 [M + H]+, 359.1283; found, 359.1288. Phenyl(5,6,7-trimethoxy-3-phenylbenzofuran-2-yl)methanone 32. Following the general procedure for direct arylation, a mixture of phenyl(5,6,7-trimethoxybenzofuran-2-yl)methanone 24 (312 mg, 1.00 mmol) and bromobenzene (0.21 mL, 2.00 mmol) was stirred for 16 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 95:5 to 85:15) to afford the desired product 32 (332 mg, 0.86 mmol, 86%) as a brown solid: mp 113 °C (recrystallized from hexane to give yellow crystals); 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J = 6.9 Hz, 2H), 7.51−7.47 (m, 3H), 7.44−7.35 (m, 5H), 6.73 (s, 1H), 4.25 (s, 3H), 3.97 (s, 3H), 3.86 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 184.8, 151.9, 147.5, 141.8, 141.6, 139.1, 137.3, 132.5, 130.9, 129.9, 129.8 (2C), 129.7 (2C), 128.4 (2C), 128.3, 128.0 (2C), 124.2, 96.2, 61.6, 60.9, 56.4; IR (CDCl3) νmax 3053, 3011, 2986, 2940, 1645, 1462, 1423, 1376, 1264, 1238,1137, 1048 cm−1; HRMS (ES+) m/z calculated for C24H21O5 [M + H]+, 389.1389; found, 389.1370. Phenyl(4,5,6-trimethoxy-3-phenylbenzofuran-2-yl)methanone 33. Following the general procedure for direct arylation, a mixture of phenyl(4,5,6-trimethoxybenzofuran-2-yl)methanone 25 (312 mg, 1.00 mmol) and bromobenzene (0.21 mL, 2.00 mmol) was

stirred for 64 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 97:3 to 95:5) to afford a mixture of the starting material 25 and the desired product 33 (326 mg, 25/33 = 1.30 determined by 1H NMR, calculated yield: 41% of 33 and 53% of 25) as a brown solid: mp 94 °C (recrystallized from hexane to give yellow crystals); 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 7.2 Hz, 2H), 7.44−7.39 (m, 3H), 7.31−7.26 (m, 5H), 6.92 (s, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.49 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 185.0, 155.8, 151.9, 148.4, 146.8, 139.5, 137.4, 132.1, 131.4, 130.3 (2C), 130.1, 129.6 (2C), 127.9 (3C), 127.4 (2C), 114.9, 91.1, 61.5, 61.3, 56.4; IR (CDCl3) νmax 2967, 2940, 2835, 1615, 1552, 1494, 1305, 1273, 1229, 1200, 1137, 1052 cm−1; HRMS (ES+) m/z calculated for C24H20O5Na [M + Na]+, 411.1208; found, 411.1199. (4-Methoxy-3-phenylbenzofuran-2-yl)(phenyl)methanone 34.41 Following the general procedure for direct arylation, a mixture of (4-methoxybenzofuran-2-yl)(phenyl)methanone 26 (252 mg, 1.00 mmol) and bromobenzene (0.21 mL, 2.00 mmol) was stirred for 64 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 99:1 to 90:10) to afford a mixture of the starting material 26 and the desired product 34 (254 mg, 26/34 = 1.15 determined by 1H NMR, calculated yield: 41% of 34 and 47% of 26) as a brown solid: mp 86 °C (recrystallized from hexane to give yellow crystals); 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J = 7.2 Hz, 2H), 7.47− 7.39 (m, 4H), 7.31−7.24 (m, 6H), 6.70 (d, J = 7.8 Hz, 1H), 3.74 (s, 3H); 13 C NMR (75 MHz, CDCl3) δ 185.7, 156.2, 155.8, 146.6, 137.2, 132.3, 131.5, 130.7 (2C), 129.64 (2C), 129.57, 129.1, 127.9 (2C), 127.7, 127.1 (2C), 117.4, 105.1, 103.9, 55.5; IR (CDCl3) νmax 3063, 2965, 2944, 1643, 1602, 1501, 1370, 1267, 1254, 1098 cm−1; HRMS (ES+) m/z calculated for C22H17O3 [M + H]+, 329.1178; found, 329.1168. (4-Hydroxy-3-phenylbenzofuran-2-yl)(phenyl)methanone 35.41 Following the general procedure for direct arylation, a mixture of (4-hydroxybenzofurane-2-yl)(phenyl)methanone 27 (186 mg, 0.78 mmol) and bromobenzene (0.165 mL, 1.56 mmol) was stirred for 16 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 98:2 to 95:5) to afford the desired product 35 (102 mg, 0.33 mmol, 42%) as a brown solid: mp 181 °C (recrystallized from hexane to give a yellow powder); 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 7.2 Hz, 2H), 7.53−7.34 (m, 9H), 7.22 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 5.26 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 185.0, 155.5, 152.1, 146.4, 137.0, 132.7, 131.3, 129.7 (2C), 129.6, 129.5 (2C), 129.0 (2C), 128.98, 128.1 (2C), 127.9, 116.1, 109.3, 104.7; IR (CDCl3) νmax 3066, 3032, 1648, 1598, 1558, 1499, 1273, 1171, 1043 cm−1; HRMS (ES+) m/z calculated for C21H15O3 [M + H]+, 315.1017; found, 315.1017. (4,6-Dimethyl-3-phenylbenzofuran-2-yl)(phenyl)methanone 36. Following the general procedure for direct arylation, a mixture of (4,6-dimethylbenzofuran-2-yl)(phenyl)methanone 28 (250 mg, 1.00 mmol) and bromobenzene (0.21 mL, 2.00 mmol) was stirred for 16 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 97:3) to afford a mixture of the starting material 28 and the desired product 36 (254 mg, 28/36 = 1.99 determined by 1H NMR, calculated yield: 33% of 36 and 65% of 28) as a yellow liquid: 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 6.9 Hz, 2H), 7.50−7.44 (m, 1H), 7.38−7.33 (m, 7H), 7.29 (s, 1H), 6.89 (s, 1H), 2.48 (s, 3H), 2.07 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 185.2, 155.1, 147.4, 138.9, 137.4, 134.0, 132.8, 132.3, 130.6, 130.0 (2C), 129.6 (2C), 127.9 (2C), 127.85, 127,80 (2C), 127.1, 124.4, 109.9, 21.8, 19.4; IR (CDCl3) νmax 3064, 3029, 2924, 1643, 1556, 1364, 1269, 1234 cm−1; HRMS (ES+) m/z calculated for C23H19O2 [M + H]+, 327.1385; found, 327.1392. Methyl 2-benzoyl-3-phenylbenzofuran-7-carboxylate 38. Following the general procedure for direct arylation, a mixture of methyl 2-benzoylbenzofuran-7-carboxylate 30 (280 mg, 1.00 mmol) and bromobenzene (0.21 mL, 2.00 mmol) was stirred for 16 h. The residue was purified by flash chromatography over silica gel (cyclohexane/ethyl acetate 95:5) to afford the desired product 38 (315 mg, 0.89 mmol, 89%) as a brown solid: mp 124 °C (recrystallized from hexane to give a yellow powder); 1H NMR (300 MHz, CDCl3) δ 8.21 (dd, J = 7.5, 1.2 Hz, 1H), 8.17 (d, J = 7.2 Hz, 2H), 7.90 (dd, J = 7.8, 1.2 Hz, 1H), 7.58− 7.54 (m, 3H), 7.48−7.41 (m, 6H), 4.04 (s, 3H); 13C NMR (75 MHz, 1325



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CDCl3) δ 184.3, 165.0, 152.5, 147.8, 136.9, 133.0, 130.7, 130.7, 130.4, 130.3 (2C), 129.9 (2C), 129.8, 128.9, 128.6, 128.4 (2C), 128.1 (2C), 123.7, 116.0, 52.4; IR (CDCl3) νmax 3069, 3032, 2954, 1720, 1651, 1298, 1215, 1141 cm−1; HRMS (ES+) m/z calculated for C23H16O4Na [M + Na]+, 379.0946; found, 379.0941.

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ASSOCIATED CONTENT S Supporting Information * Experimental procedures, characterization data, and 1H and 13C spectra for new compounds are included. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. ACKNOWLEDGMENTS This work was financially supported by the Centre National de la Recherche Scientifique, the Institut Curie, and the Agence Nationale de la Recherche (Grant ANR-08-PCVI-0031CHEMISPIKE).

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Palladium-Catalyzed Direct Arylation of Polysubstituted Benzofurans

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